Most drugs given orally are tablets or capsules containing beads, which must dissolve before absorption through the intestinal wall can occur. It is sometimes desirable in the case of a particular drug or a particular therapeutic situation to control the dissolution of the dosage form, i.e. prepare it such that it is immediately-released, or its release is delayed or sustained to maintain certain plasma levels.
In general, drug absorption is relatively slow in the stomach, becomes rapid in the small intestine, and sharply declines in the large intestine. Oftentimes, this drug absorption difference in various gastrointestinal segments is ignored when designing a drug product. For example, an oral drug product with a pH-independent, zero-order dissolution profile is commonly considered ideal. However, this type of product design may suffer from a lower bioavailability, due to the entombment of the drug in fecal material and the low absorption in the large intestine. That is, a significant portion of the drug may still be present after passing through the small intestine, and that portion does not have a good chance of being absorbed. The large intestine is concerned primarily with absorption of water and the secretion of mucous to aid the intestinal contents to slide down the intestinal tube. Because of a low absorptive area and lack of villi/microvilli structures, the absorption of nutrients and drugs is not the major function of the large intestine. A high amount of undissolved drug in the large intestine may lead to a significant bioavailability reduction.
Compensation for changing absorption characteristics in the gastrointestinal track may be important for some drugs. It is rational for a delivery system to pump out the drug much faster when the system reaches the distal segment of the intestine to avoid the drug entrapment in the feces. By using a combination of two or more enteric materials to form a membrane-controlled or a matrix-controlled dosage form, the duration of a drug can be prolonged and the amount of the unabsorbed drug in the lower intestine, due to the entrapment of the drug and sharply declining absorption characteristics in large intestine, can be minimized.
The present invention provides formulations designed to optimize (i.e. accelerate) absorption in the small intestine in order to overcome this problem of “dose-dumping”.
While there are numerous formulations for sustained release and delayed release, it is believed that the present inventors for the first time address the problem of poor bioavailability of a drug or drugs in an oral dosage form due to pH changes in the intestinal lumen. As mentioned above, prior controlled release forms were focused on maintenance of blood levels of the active substance or substances, either for therapeutic purposes or to reduce side effects. For instance, U.S. Pat. No. 6,068,859, discloses controlled-release oral dosage forms that will reduce side effects, which are made in such a manner that most of the drug is released distal to the duodenal portion of the small intestine. One alternative disclosed therein is the preparation of an oral dosage form that combines sustained release properties with delayed release characteristics for the drug, azithromycin. This approach gives a sustained released profile after an enteric delay period. The sustained release properties, however, are not pH-dependent. In other words, the system failed to provide an accelerated dissolution profile at higher pH and may suffer a significant bioavailability loss if the active pharmaceutical ingredient in the system has low permeability in the lower gastrointestinal tract.